1. university of Zabol 2. Tehran University of Medical Science 3. university of Zabol
Aging is one of the most important factor in the development of alzheimers disease (ad). the important pathologic protein involved in the development of ad is tau. although the role of autophagy in ad has been relatively proven, the effect of longevity on tau neurotoxicity are under debates. one key question of debate, however, is which of these pathologies (aging or tauopathy) appears first and hence is upstream in the pathocascade. in this study we analyzed the effects of longevity on expression of mammalian target of rapamycin (mtor) and their relation with tau toxicity in drosophila melanogaster ad model.
The strains usa-tau r406w, the eye (gmr-gal4), ok107- gal4, and pan-neural (elav-gal4) driver strains, were obtained from the bloomington drosophila stock center (flystocks.bio.indiana.edu). homozygous virgin females ok107-gal4 were mated with males bearing uas-tau constructs (for tau expression in brain neurons), and the progeny was maintained at 270c. for transgene expression in the eye, homozygous females gmr-gal4 uas-tau were crossed with males carrying the desired constructs and the progeny was maintained at 27.50c. for histological study of retinas, paraffin-embedded heads of 10, 20 or 30-day-old flies after progeny were sectioned at 1 mm and analyzed. at mentioned time points flies were also unseized with co2, and total rna was isolated from 45 fly heads, and cdnas were prepared. expression of tau and mtor in brain of flies were evaluated via real-time pcr using specific primer sets.
As predicted, tau over expressed in the brain neurons and constantly induced cell toxicity and ad phenotypes in flies according to behavior and histological assessments. our results have been shown that, expression of important anti-autophagy marker mtor was significantly decreased with tauopathy in flys brain. on the other hand, there was no change observed in mtor expression with aging process in this model of ad.
A growing list of evidence suggests that mtor signaling influences longevity and aging. inhibition of the mtor complex 1 (mtorc1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied. tauopathy-induced up-regulation of mtor in this model may be related to activation of autophagy and endogenous resistance mechanisms against tau neurotoxicity. finally, it proposed that the expression of autophagy related proteins (lc3, atg and beclin 1) and 5 amp activated protein kinase (ampk) activity also should be analyzed for confirmation of our data.